This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Methamphetamine use is increasingly prevalent in the US and is associated with serious medical and psychiatric problems. There has also been a significant increase in the number of patients entering treatment for methamphetamine dependence, however, no pharmacologic treatment has been identified as robustly efficacious in treating methamphetamine dependent individuals to date. Given that withdrawal from amphetamine is thought to contribute to relapse to methamphetamine use during early treatment, it is important to examine potential pharmacologic agents for alleviating withdrawal. Thus, this study is designed to establish a methamphetamine withdrawal paradigm in humans. To this end, 30 methamphetamine dependent participants (ages 18-65 yrs) will be entered into a 4-week residential study. Urine samples will be obtained at baseline to ensure recent methamphetamine use. Intake assessments will include cognitive testing, standardized assessment of depression and anxiety, profile of mood states, methamphetamine selective severity assessment, methamphetamine withdrawal assessment, sleep quality and quantity, a pre-attentional measure (P50 potential amplitude assesses level of arousal in brainstem-thalamic processes, and habituation to paired stimulation determines sensory gating capacity) and attentional measure (performance on psychomotor vigilance task-PVT, a prototypical measure of thalamocortical attentional systems). Upon admission to the residential facility, all study participants will be started on (20-30mg) long acting amphetamine/d-amphetamine and stabilized over the first 5 days. After stabilization participants will be randomized based on sex, amphetamine withdrawal questionnaire score, and methamphetamine selective severity assessment score to either continued treatment with amphetamine/d-amphetamine or placebo for 2 weeks. All subjects will then be placed on placebo for the last 7 days. Intake Assessments will be repeated at least thrice weekly, except for pre-attentional and attentional measures that will be repeated weekly, during the course of the study. All subjects will participate in standard substance abuse treatment as provided by the residential treatment facility and earn monetary compensation for participation. The primary outcomes of interest include retention in treatment, measures of methamphetamine withdrawal, cognitive assessments, and performance on quantitative pre-attentional and attentional neurophysiological measures. Results of this study will support an independent grant submission to NIDA to examine potential pharmacological agents for treating methamphetamine withdrawal.